Abstract
Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into PHFs is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fibre diffraction, we have characterised the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulphide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a C322A substitution. We show that disulphide bond formation inhibits assembly and that the C322A variant rapidly forms long and highly ordered PHFs.
Original language | English |
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Pages (from-to) | 3650-3665 |
Number of pages | 16 |
Journal | Journal of Molecular Biology |
Volume | 429 |
Issue number | 23 |
Early online date | 15 Sep 2017 |
DOIs | |
Publication status | Published - 24 Nov 2017 |
Keywords
- Journal Article
- Alzheimer's disease
- tau
- neurofibrillary tangles
- paired helical filaments
- disulfide
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Profiles
-
Charles Harrington
- Clinical Medicine
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Senior Research Fellow
- Institute of Medical Sciences
Person: Academic Related - Research